Project Summary Protein-protein interactions (PPIs) are at the heart of almost every biological process. Therefore, there is great interest in the discovery of chemical probes that potently and selectively antagonize PPIs. This generally requires chemical matter quite different than the Lipinski-compliant small molecules typically employed to antagonize enzyme active sites. This project will create a novel library of millions of DNA-encoded, cell permeable macrocycles, which will serve as a rich source of PPI inhibitors. A model screen will be done to identify inhibitors of the interaction of Rpn13 and Uch37, two interesting proteins in the proteasome. Deluge will make this library and an optimized screening protocol available to customers in an easy to use format, empowering them to carry out their own screening campaigns, with the company providing informatics and chemistry support afterwards. This effort is expected to stimulate the discovery of interesting PPI inhibitors of interest to the biomedical research community in a way that is commercially attractive to Deluge.